The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK and NIMH, is the synthesis and evaluation of analogs of GBR12909 as putative cocaine antagonists. This project has identified several promising novel agents, including the most selective dopamine uptake inhibitor reported. Other studies show that GBR12909 suppresses cocaine self-administration in Rhesus monkeys, supporting its potential use in the treatment of cocaine addiction and blocks the cocaine-induced increase in extracellular DA as measured by in vivo microdialysis. Another component involves investigation of the possible heterogeneity of DA transporter binding sites. This project has identified three binding sites for the DA transporter ligands [3H]GBR12935, [3H]BTCP, and a single binding site for [3H]mazindol. Another component of this project addresses the role of classical conditioning in cocaine-induced behavioral sensitization. These studies demonstrated that associative learning mechanisms are involved in the acquisition of context-specific behavioral sensitization to cocaine. Studies with genetically inbred strains of mice showed that the occurrence of sensitization is not correlated with either the potency or efficacy of cocaine as a motoric stimulant. Preliminary human studies failed to demonstrate cocaine- sensitization with a one day training paradigm (ARC-174). Clinical protocols, currently underway, 1) test the DA hypothesis of cocaine addiction by acute administration of cocaine to subjects who are on various DA receptor antagonists (ARC-170); and 2) attempt to develop a human model of context-specific behavioral sensitization to cocaine (ARC- 174). The significance of these findings to drug abuse research is that increased understanding of how cocaine works will lead to the development of improved treatments.